Cannabimimetic indole derivatives

ABSTRACT

Cannabimimetic indole derivatives are presented which have preferentially high affinities for one of the cannabinoid CB1 or CB2 receptor sites. The improved receptor affinity makes these analogs therapeutically useful as medications in individuals and animals.

This application is a divisional of U.S. application Ser. No.10/111,059, filed Oct. 21, 2002, now U.S. Pat. No. 6,900,236 which isthe national phase of International Application No. PCT/US00/28832,filed Oct. 18, 2000, which claims the benefit of U.S. Provisional PatentApplication No. 60/159,997, filed Oct. 18, 1999, the contents of each ofwhich are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to cannabinoid analogs and ismore particularly concerned with new and improved indole cannabinoidanalogs exhibiting high binding affinities for cannabinoid receptors,pharmaceutical preparations employing these analogs and methods ofadministering therapeutically effective amounts of the preparations toprovide a physiological effect.

BACKGROUND OF THE INVENTION

Classical cannabinoids such as the marijuana derived cannabinoidΔ⁹-tetrahydrocannabinol, (Δ⁹-THC) produce their pharmacological effectsvia interaction with specific cannabinoid receptors in the body. So far,two cannabinoid receptors have been characterized: CB1, a centralreceptor found in the mammalian brain and peripheral tissues and CB2, aperipheral receptor found only in the peripheral tissues. Compounds thatare agonists or antagonists for one or both of these receptors have beenshown to provide a variety of pharmacological effects. See, for example,Pertwee, R. G., Pharmacology of cannabinoid CB1 and CB2 receptors,Pharmacol. Ther., (1997) 74:129–180 and Di Marzo, V., Melck, D.,Bisogno, T., DePetrocellis, L., Endocannabinoids: endogenous cannabinoidreceptor ligands with neuromodulatory action, Trends Neurosci. (1998)21:521–528.

There is considerable interest in developing cannabinoid analogspossessing high affinity for one of the CB1 or CB2 receptors and/ormetabolic stability. Such analogs may offer a rational therapeuticapproach to a variety of disease states. One class of cannabimimeticanalogs encompasses indole derivatives such as the well knownaminoalkylindoles represented by WIN 55212-2{(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naptha-lenyl)methanone}.Aminoalkylindoles of this type typically have a carbon linkedalkylheterocyclic substituent at the indole-1 position, which isbelieved to be important for their canabimimetic activities. These knownmaterials are not selective for preferential activation of one of theCB1 or CB2 receptors.

SUMMARY OF THE INVENTION

Aminoalkylindoles have been found to act as agonists for the CB1 and CB2receptors and occasionally as antagonists for the CB1 and CB2 receptors.The invention includes compounds selective for either the CB1 or CB2receptors. Further, some of the compounds have agonistic or antagonisticproperties.

One aspect of the invention includes several novel aminoalkylindolecannabinoid analogs and physiologically acceptable salts thereof. In oneembodiment of the invention, straight carbon chains were introduced tothe indole-1 position. Different functional groups were also introducedto the straight carbon chains. This embodiment is shown as A.

Z may be in the 4-, 5-, 6- or 7-position and is selected from the groupconsisting of nitro; nitroso; amino; alkylamino; dialkylamino; azido(N₃); cyano; isothiocyano and phenyl.

X is selected from the group consisting of halogen; hydrogen; hydroxy;low alkanoate; formyl; amino; cyano; isothiocyano and azido.

R₁ is selected from the group consisting of saturated or unsaturatedstraight carbon chains with a maximum length of seven carbon atoms;saturated or unsaturated branched carbon chains with a maximum length ofseven carbon atoms; cyclic aliphatic rings interconnected to theindole-1 position with one or two carbon atoms; bicyclic aliphatic ringsinterconnected to the indole-1 position with one or two carbon atoms;and heterocyclic rings interconnected to the indole-1 position with oneor two carbon atoms.

R₂ is selected from the group consisting of H and lower alkyl.

Y is selected from the group consisting of carbonyl and CH═CH (cis ortrans).

R₃ is selected from the group consisting of phenyl; napthyl;9-anthracenyl; phenyl with no more than two substituents selected fromthe group consisting of halogen, nitro, nitroso, amino, alkylamino,dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano andisothiocyano; napthyl with no more than two substituents selected fromthe group consisting of halogen, nitro, nitroso, amino, alkylamino,dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano andisothiocyano; and 9-anthracenyl with no more than two substituentsselected from the group consisting of halogen, nitro, nitroso, amino,alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyanoand isothiocyano.

The analogs of this embodiment show high binding affinities for the CB1and CB2 cannabinoid receptors. More importantly, some of these compoundsshow not only comparable cannabimimetic activity with the compound WIN55212-2 but also a surprisingly higher selectivity for one of the CB1 orCB2 receptors. More specifically, the inventive analogs showed similaror higher receptor binding affinity than the well-known indolecannabinoid WIN 55212-2.

Another embodiment of the invention is shown as B. In this embodimentthe functionalities of the novel cannabimimetic indole analogs weremodified in the indole-3 and/or indole-6 positions.

Z may be in the 4-, 5-, 6- or 7-position and is selected from the groupconsisting of halogen; hydroxy; methoxy and lower alkyl.

X is selected from the group consisting of hydrogen; hydroxy; loweralkanoate; formyl; amino; cyano and isothiocyano.

R₁ is selected from the group consisting of saturated or unsaturatedstraight carbon chains with a maximum length of seven carbon atoms;saturated or unsaturated branched carbon chains with a maximum length ofseven carbon atoms; cyclic aliphatic rings interconnected to theindole-1 position with one or two carbon atoms; and bicyclic aliphaticrings interconnected to the indole-1 position with one or two carbonatoms.

R₂ is selected from the group consisting of H and lower alkyl.

Y is selected from the group consisting of carbonyl and CH═CH (cis ortrans).

R₃ is selected from the group consisting of phenyl; napthyl;9-anthracenyl; phenyl with no more than two substituents selected fromthe group consisting of halogen, nitro, nitroso, amino, alkylamino,dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano andisothiocyano; napthyl with no more than two substituents selected fromthe group consisting of halogen, nitro, nitroso, amino, alkylamino,dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano andisothiocyano, and 9-anthracenyl with no more than two substituentsselected from the group consisting of halogen, nitro, nitroso, amino,alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyanoand isothiocyano.

The analogs of this embodiment are surprisingly potent cannabimimeticcompounds with high CB1 and/or CB2 selectivity.

Since CB2 selective cannabinoids are able to activate the CB2 receptorand thereby modulate the immune system with little psychoactivity orother CNS effects, these analogs are possible therapeutic agents.Additionally, some of the iodide and fluoride containing analogs arepotential radioactive probes for imaging in vivo the distribution ofcannabinoid receptors. The azido modified analogs are excellent affinityprobes for characterizing binding pockets of cannabinoid receptors.

The analogs disclosed herein are relatively easy to manufacture.Additionally these analogs have better physiochemical properties thannaturally occurring cannabinoids. Thus, the novel cannabimimetic indolederivatives described herein, and physiologically acceptable saltsthereof, represent potentially useful materials for providing aphysiological effect to treat pain, peripheral pain, glaucoma, epilepsy,nausea such as associated with cancer chemotherapy, AIDS WastingSyndrome, cancer, neurodegenerative diseases including MultipleSclerosis, Parkinson's Disease, Huntington's Chorea and Alzheimer'sDisease, mental disorders such as Schizophrenia and depression; toprevent or reduce endotoxic shock and hypotensive shock; to modulateappetite; to reduce fertility; to prevent or reduce diseases associatedwith motor function such as Tourette's syndrome; to prevent or reduceinflammation; to provide neuroprotection and to effect memoryenhancement.

The novel cannabimimetic indole derivatives described herein alsoprovide useful materials for testing the cannabinoid system. Thus,another aspect of the invention is the administration of atherapeutically effective amount of an inventive compound, or aphysiologically acceptable salt thereof, to an individual or animal toprovide a physiological effect.

DESCRIPTION OF SOME PREFERRED EMBODIMENTS

As used herein, a “therapeutically effective amount” of a compound, isthe quantity of a compound which, when administered to an individual oranimal, results in a sufficiently high level of that compound in theindividual or animal to cause a discernible increase or decrease instimulation of cannabinoid receptors. Physiological effects that resultfrom cannabinoid receptor stimulation include analgesia, decreasednausea resulting from chemotherapy, sedation and increased appetite.Other physiological functions include relieving intraocular pressure inglaucoma patients and suppression of the immune system. Typically, about10 mg/day to about 1,000 mg/day is a possible “therapeutically effectiveamount” for the inventive compounds.

As used herein, an “individual” refers to a human. An “animal” refersto, for example, veterinary animals, such as dogs, cats, horses and thelike, and farm animals, such as cows, pigs and the like.

The compound of the present invention can be administered by a varietyof known methods, including orally, rectally, or by parenteral routes(e.g., intramuscular, intravenous, subcutaneous, nasal or topical). Theform in which the compounds are administered will be determined by theroute of administration. Such forms include, but are not limited to,capsular and tablet formulations (for oral and rectal administration),liquid formulations (for oral, intravenous, intramuscular orsubcutaneous administration) and slow releasing microcarriers (forrectal, intramuscular or intravenous administration). The formulationscan also contain a physiologically acceptable vehicle and optionaladjuvants, flavorings, colorants and preservatives. Suitablephysiologically to acceptable vehicles may include, for example, saline,sterile water, Ringer's solution, and isotonic sodium chloridesolutions. The specific dosage level of active ingredient will dependupon a number of factors, including, for example, biological activity ofthe particular preparation, age, body weight, sex and general health ofthe individual being treated.

The inventive cannabinoid analogs are generally described by thestructural formulas previously disclosed. The following examples aregiven for purposes of illustration only in order that the presentinvention may be more fully understood. These examples are not intendedto limit in any way the practice of the invention. The preparedcannabimimetic indole derivatives can generally be described withreference to structural formulas 1 and 2 below and includephysiologically acceptable salts thereof.

The inventive cannabimimetic indole derivatives of structural formula 1include both racemics and two enantiomers.

Z is in the indole-6 position and is selected from the group consistingof H; NO₂; NH₂; N₃ and NCS.

R₁ is a heterocyclic ring interconnected to the indole-1 position withone carbon atom.

X is hydrogen.

R₂ is selected from the group consisting of H and methyl.

Y is carbonyl.

R₃ is selected from the group consisting of phenyl; napthyl;adamantanyl; pyrenyl and substituted versions of any of the above.

The inventive materials of structural formula 1 are listed in TABLE 1.It should be noted that R₁ for all of the materials of TABLE 1 was1-(N-Methyl-2-piperidinyl)methyl. All of the materials of TABLE 1 have achiral center and the binding affinities of the materials of TABLE 1were obtained by evaluating their racemic samples.

TABLE 1 K_(l) nM analog Z R₂ R₃ CB1 CB2 AM664 NO₂ CH₃ 2-iodophenyl 4080.0 AM665 NH₂ CH₃ 2-iodophenyl 206 20.3 AM671 N₃ CH₃ Phenyl 155 59.1AM684 NCS CH₃ Phenyl 181 44.8 AM1215 N₃ CH₃ 2-iodophenyl 40.7 21.9AM1216 NCS CH₃ 2-iodophenyl 210 25.2 AM2209 N₃ H 5-azido-2-iodophenyl48.8 41 .8 AM2223 NCS H 5-isothiocyanato-2- 64.8 29.9 iodophenyl AM1221NO₃ CH₃ 1-naphthyl 52.3 0.28 AM1225 NH₃ CH₃ 1-naphthyl 439.6 38.5 AM1231N₃ CH₃ 1-naphthyl 31.2 34.2 AM1218 NO₂ H 1-naphthyl 11.2 3.98 AM1219 NH₂H 1-naphthyl 96.6 31.3 AM1224 N₃ H 1-naphthyl 20.2 0.73 AM1217 NCS H1-naphthyl 255 81.5 AM1299 H H 4-nitro-1-naphthyl 12.4 13.5 AM1296 H H1-naphthyl 7.57 3.88 AM1220 H H 1-naphthyl 3.88 73.4 AM2212 N₃ H4-iodo-1-naphthyl 31.0 2.90 AM2215 NCS H 4-isothiocyanato-1-naphthyl 23599.6 AM1248 H H adamantanyl 100 332 AM1253 H H 2-pyrenyl 60.3 126

Z is in the indole-6 position and is selected from the group consistingof hydrogen; NO₂; NH₂ and halogen.

X is selected from the group consisting of halogen; H; OH; OCOCH₃; OTs;NCS; OAc and CN.

R₁ is a saturated lower alkane with a maximum length of seven carbonatoms.

R₂ is selected from the group consisting of H and methyl.

Y is carbonyl.

R₃ is selected from the group consisting of phenyl; napthyl; andsubstituted versions of any of the above.

The inventive materials of structural formula 1 are listed in TABLE 2.R₁ lists the number of carbon atoms in the chain at that position.

TABLE 2 K_(l) nM analog Z R₁ X R₂ R₃ CB1 CB2 AM683 H 4 H CH₃2-iodophenyl 272 281 AM669 H 5 H CH₃ 2-iodophenyl 47.2 38.6 AM682 H 6 HCH₃ 2-iodophenyl 332 693 AM672 H 7 H CH₃ 2-iodophenyl 1603 1511 AM689 H5 OCOCH₃ CH₃ 2-iodophenyl 2279 1019 AM690 H 5 OH CH₃ 2-iodophenyl 48501972 AM2227 H 5 OTs CH₃ 2-iodophenyl 1024 2968 AM2229 H 5 I CH₃2-iodophenyl 116.5 46.2 AM2230 H 5 NCS CH₃ 2-iodophenyl 195 29.5 AM2225H 5 F CH₃ 2-iodophenyl 5.97 3.8 AM679 H 5 H H 2-iodophenyl 13.5 49.5AM692 H 5 OCOCH₃ H 2-iodophenyl 2656 1519 AM693 H 5 OH H 2-iodophenyl835 526 AM697 H 5 OTs H 2-iodophenyl 1306 1116 AM698 H 5 I H2-iodophenyl 135.8 314.7 AM1201 H 5 NCS H 2-iodophenyl 106 110 AM694 H 5F H 2-iodophenyl 0.08 1.44 AM1202 H 5 H H 2-iodo-5-nitrophenyl 98.9 22.9AM1203 H 5 H H 2-iodo-5-aminophenyl 63.6 88.9 AM1204 H 5 H H2-iodo-5-isothiocyanophenyl 5659 3353 AM1205 H 5 H H2-iodo-5-azidophenyl 116.9 195.7 AM1206 H 5 H H 2,5-diiodophenyl 105.1150.5 AM1284 H 3 OCOCH₃ H 1-naphthyl 126.8 102.8 AM1289 H 3 OTs H1-naphthyl 359.6 78.64 AM1292 H 3 I H 1-naphthyl 3.1 18.1 AM1294 H 3 NCSH 1-naphthyl 283.3 237.3 AM1282 H 4 OCOCH₃ H 1-naphthyl 133.4 100.8AM1283 H 4 OH H 1-naphthyl 117.2 196.5 AM1286 H 4 OTs H 1-naphthyl 15091289 AM1288 H 4 I H 1-naphthyl 1.3 10.5 AM1291 H 4 NCS H 1-naphthyl 29581804 AM1295 H 4 F H 1-naphthyl 2.5 30.7 AM2232 H 4 CN H 1-naphthyl 0.281.48 AM2231 NO₂ 4 CN H 1-naphthyl 4.90 23.9 AM2202 H 5 OH H 1-naphthyl33.1 110.6 AM2203 H 5 I H 1-naphthyl 7.8 45.8 AM2204 H 5 NCS H1-naphthyl 7.5 24.4 AM2201 H 5 F H 1-naphthyl 1.0 2.6 AM1233 NO₂ 5 OAc H1-naphthyl 141.7 153.9 AM1234 NO₂ 5 OH H 1-naphthyl 77.6 196.8 AM1235NO₂ 5 F H 1-naphthyl 1.5 20.4 AM1236 NH₂ 5 OAc H 1-naphthyl 1127 558.8AM1237 NH₂ 5 OH H 1-naphthyl 836.8 244.4 AM1238 I 5 OH H 1-naphthyl 3.117.3 Am1230 I 5 F H 1-naphthyl 1.1 2.4 AM2210 H 4 I H 4-nitro-1-naphthyl1.8 11.3 AM2213 H 4 I H 4-azido-1-naphthyl 3.0 30 AM2216 H 4 I H4-isothicocyano-1-napthyl 42.4 213 AM1256 H 5 H CH₃4-dimethylamino-1-naphthyl 4.74 18.6

The above materials were generally prepared as follows.

A. General Preparation Procedures for Materials Listed in Table 2

The materials listed in Table 2 can be prepared by methods outlined inScheme 1.

When Z=NO₂, the structures can be transformed to the differentsubstituents as listed in Table 2 using methods outlined in Scheme 2.

The commercially unavailable R3-COCl used in Scheme 1 can be preparedaccording to Scheme 3.

After these acid chlorides were connected to indole 3-position, thenitro group in them can be further transformed into amino, iodo, azido,and isothiocyanate groups according to the methods outlined in Scheme 4.

B. General Preparation Procedures for Materials Listed in Table 1

These materials can be prepared in similarly manners as those compoundslisted in Table 2 by using N-methyl-2-piperidinemethyl chloride insteadof acetoxylalkylhalides for the alkylation of indole 1-position inScheme 1.

Examples of specific analogs were prepared as follows:

3-Acyl-1H-indole. 17.5 ml of a 3M solution of methyl magnesium bromidein ethyl ether was added dropwise with stirring to a solution of indole(5.85 g, 50 mmol) in 50 mL of ethyl ether at 0° C. After addition, thereaction mixture was warmed up to room temperature and stirred for 2hours (h). Then the reaction mixture was cooled down again to 0° C. andto it was added slowly with violent stirring a solution of acyl chloride(50 mmol) in 50 mL of ethyl ether. The resulting reaction mixture waswarmed up to room temperature and stirred for another 1 h followed bythe slow addition of 375 ml of ammonium chloride aqueous solution. Afterviolently stirring for 30 min, a white solid was formed and filtrated.The filtrate was washed successively with ethyl ether and recrystallizedfrom ethyl acetate:hexane to afford the product.

2-methyl-3-acyl-1H-indole. The foregoing procedure was repeated using2-methyl indole in place of indole.

1-Alkyl-2-methyl-3-acyl-1H-indole. To a 1.2 mmol suspension of sodiumhydride (48 mg, 60% in mineral oil) in 2 mL of dimethylformamide (DMF)was added 2-methyl-3-acyl-1H-indole (0.4 mmol). After stirring at roomtemperature for 30 min, alkyl bromide (0.6 mmol) was added dropwise. Theresulting mixture was heated to 65° C. and stirred for 3 h followed byremoval of solvent under vacuum. The residue was separated by flashcolumn chromatography (silica gel, petroleum ether-ethyl acetate, 5:1,v/v) to afford the product.

A person of ordinary skill in the art, understanding the disclosures forthe general preparation and specific preparation examples would know howto modify the disclosed procedures to achieve the above listed analogs.

The materials were tested for CB2 receptor binding affinity and for CB1receptor affinity (to determine selectivity for the CB2 receptor). Asused herein, “binding affinity” is represented by the IC₅₀ value whichis the concentration of an analog required to occupy the 50% of thetotal number (Bmax) of the receptors. The lower the IC₅₀ value thehigher the binding affinity. As used herein an analog is said to have“binding selectivity” if it has higher binding affinity for one receptorcompared to the other receptor; e.g. a cannabinoid analog which has anIC₅₀ of 0.1 nM for CB1 and 10 nM for CB2, is 100 times more selectivefor the CB1 receptor. The binding affinities (K_(i)) are expressed innanomoles (nM) and are listed in TABLE 1 and TABLE 2 above.

For the CB1 receptor binding studies, membranes were prepared from ratforebrain membranes according to the procedure of P. R. Dodd et al, ARapid Method for Preparing Synaptosomes: Comparison with AlternativeProcedures, Brain Res., 107–118 (1981). The binding of the novelanalogues to the CB1 cannabinoid receptor was assessed as described inW. A. Devane et al, Determination and Characterization of a CannabinoidReceptor in a Rat Brain, Mol. Pharmacol., 34, 605–613 (1988) and A.Charalambous et al, 5′-azido Δ ⁸ THC: A Novel Photoaffinity Label forthe Cannabinoid Receptor, J. Med. Chem., 35, 3076–3079 (1992) with thefollowing changes. The above articles are incorporated by referenceherein.

Membranes, previously frozen at −80° C., were thawed on ice. To thestirred suspension was added three volumes of TME (25 mM Tris-HClbuffer, 5 mM MgCl₂ and 1 mM EDTA) at a pH 7.4. The suspension wasincubated at 4° C. for 30 min. At the end of the incubation, themembranes were pelleted and washed three times with TME.

The treated membranes were subsequently used in the binding assaydescribed below. Approximately 30 μg of membranes were incubated insilanized 96-well microtiter plate with TME containing 0.1% essentiallyfatty acid-free bovine serum albumin (BSA), 0.8 nM [³H] CP-55,940, andvarious concentrations of test materials at 200° C. for 1 hour. Thesamples were filtered using Packard Filtermate 196 and Whatman GF/Cfilterplates and washed with wash buffer (TME) containing 0.5% BSA.Radioactivity was detected using MicroScint 20 scintillation cocktailadded directly to the dried filterplates, and the filterplates werecounted using a Packard Instruments Top-Count. Nonspecific binding wasassessed using 100 nM CP-55,940. Data collected from three independentexperiments performed with duplicate determinations was normalizedbetween 100% and 0% specific binding for [³H] CP-55,940, determinedusing buffer and 100 nM CP-55,940. The normalized data was analyzedusing a 4-parameter nonlinear logistic equation to yield IC₅₀ values.Data from at least two independent experiments performed in duplicatewas used to calculate IC₅₀ values which were converted to K_(i) valuesusing the assumptions of Cheng et al, Relationship Between theInhibition Constant (K _(i)) and the concentration of Inhibitor whichcauses 50% Inhibition (IC ₅₀) of an Enzymatic Reaction, Biochem.Pharmacol., 22, 3099–3102, (1973), which is incorporated by referenceherein.

For the CB2 receptor binding studies, membranes were prepared fromfrozen mouse spleen essentially according to the procedure of P. R. Doddet al, A Rapid Method for Preparing Synaptosomes: Comparison withAlternative Procedures, Brain Res., 226, 107–118 (1981) which isincorporated by reference herein. Silanized centrifuge tubes were usedthroughout to minimize receptor loss due to adsorption. The CB2 bindingassay was conducted in the same manner as for the CB1 binding assay. Thebinding affinities (K_(i)) were also expressed in nanomoles (nM).

The physiological and therapeutic advantages of the inventive materialscan be seen with additional reference to the following references, thedisclosures of which are hereby incorporated by reference. Arnone M.,Maruani J., Chaperon P, et al, Selective inhibition of sucrose andethanol intake by SR141716, an antagonist of central cannabinoid (CB1)receptors, Psychopharmacal, (1997) 132, 104–106. Colombo G, Agabio R,Diaz G. et al: Appetite suppression and weight loss after thecannabinoid antagonist SR141716. Life Sci. (1998) 63-PL13-PL117. SimiandJ, Keane M, Keane P E, Soubrie P: SR 141716, A CB1 cannabinoid receptorantagonist, selectively reduces sweet food intake in marmoset. Behav.Pharmacol (1998) 9:179–181. Brotchie J M: Adjuncts to dopaminereplacement a pragmatic approach to reducing the problem of dyskinesiain Parkinson's disease. Mov. Disord. (1998) 13:871–876. Terranova J-P,Storme J-J Lafon N et al: Improvement of memory in rodents by theselective CB1 cannabinoid receptor antagonist, SR 141716.Psycho-pharmacol (1996) 126:165–172. Hampson A L Grimaldi M. Axpirod J.Wink D: Cannabidiol and (−) Δ⁹ tetrahydrocannabinol are neuroprotectiveantioxidants. Proc. Natl Acad Sci. USA (1998) 9S:8268–8273. Buckley N E,McCoy K I, Mpzey E et al Immunomodulation by cannabinoids is absent inmice deficient for the cannabinoid CB ₂ receptor. Eur. J Pharmacol(2000) 396:141–149. Morgan Dr: Therapeutic Uses of Cannabis. HarwoodAcademic Publishers, Amsterdam. (1997). Joy J E, Wagtson S J, Benson JA: Marijuana and Medicine Assessing the Science Base. National AcademyPress, Washington, D.C., USA (1999). Shen M. Thayer S A: Cannabinoidreceptor agonists protect cultured rat hippocampal neurons fromexcitotoxicity. Mol. Pharmacol (1996) 54:459–462. DePetrocellis L, MelckD, Palmisano A. et al: The endogenous cannabinoid anandamide inhibitshuman breaast cancer cell proliferation. Proc Natl. Acad. Sci USA (1998)95:8375–8380. Green K. Marijuana smoking vs. cannabinoids for glaucomatherapy. Arch. Ophibalmol. (1998) feb 433–1437. Hemming M, Yellowlees PM, Effective treatment of Tourette's syndrome with marijuana. J.Psychopharmacol, (1993) 7:389–391. Muller-Vahl K B, Schneider U, KolbeH, Emrich, H M. Treatment of Tourette's syndrome withdelta-9-tetrahydrocannabinol. Am. J. Psychiat. (1999) 156–195.Muller-Vahl K B, Kolbe H, Schneider U, Emrich, H M Cannabis in movementdisorders. Porsch. Kompicmentarmed (1999) 6 (suppl. 3) 23–27. Consroe P,Musty R, Rein J, Tillery W, Pertwee R. The perceived effects of smokedcannabis on patents with multiple sclerosis, Eur. Neurol. (1997)38-44-48. Pinnegan-Ling D, Musty R. Marinol and phantom limb pain: acase study. Proc Inv. Cannabinoid Rea. Sec. (1994):53. Brenneisen R,Pgli A, Elsohly M A, Henn V. Spiess Y: The effect of orally and rectallyadministered Δ ⁹⁻ tetrahydrocannabinol on spasticity, a pilot study with2 patients. Int. J. Clin Pharmacol Ther. (1996) 34:446–452. Martyn C N.Illis L S, Thom J. Nabilone in the treatment of multiple sclerosis.Lancet (1995) 345:579. Maurer M, Henn V, Dittrich A, Hofmann A.Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects ina single case double-blind trial. Eur. Arch. Psychiat. Clin. Neurosci.(1990), Z40:1–4. Herzberg U, Eliav E, Bennett G J, Kopin I J: Theanalgesic effects of R(+) WIN 55,212-2 mesylate, a high affinitycannabinoid agonist in a rare model of neuropathic pain. Neurosci.Letts. (1997) 221:157–160. Richardson J D, Kilo S. Hargreaves K M,Cannabinoids reduce dryperalgesia and inflammation via interaction withperipheral CB1 receptors. Pain (1998) 75:111–119. Ricardson J D,Aanonsen I, Hargreaves K M: Antihyperalgesic effects of a spinalcannabinoids. Eur. J. Pharmacol. (1998) 346:145–153. Calignano A, LaRana G. Diuffrida A, Piomelli D: Control of pain initiation byendogenous cannabinoids. Nature (1998) 394:277–291. Wagner J A, Varga K,Jarai Z, Kunos G: Mesenteric vasodilation mediated by endotheliaanandamide receptors. Hypertension (1999) 33:429–434. Schuel, H.,Burkman, L. J., Picone, R. P., Bo, T., Makriyannis, A., Cannabinoidreceptors in human sperm. Mol. Biol. Cell., (1997) (8), 325a.

As can be seen from the results in the TABLES, some of the compounds,for example, AM1295, AM1235, AM1288 and AM694, show a high selectivityfor the CB1 receptor. Other compounds, for example, AM2230, AM1289, andAM1237, show a high selectivity for the CB2 receptor. The inventiveanalogs described herein, and physiologically acceptable salts thereof,have high potential when administered in therapeutically effectiveamounts for providing a physiological effect useful to treat pain,peripheral pain, glaucoma, epilepsy, nausea such as associated withcancer chemotherapy, AIDS Wasting Syndrome, cancer, neurodegenerativediseases including Multiple Sclerosis, Parkinson's Disease, Huntington'sChorea and Alzheimer's Disease, mental disorders such as Schizophreniaand depression; to prevent or reduce endotoxic shock and hypotensiveshock; to modulate appetite; to reduce fertility; to prevent or reducediseases associated with motor function such as Tourette's syndrome; toprevent or reduce inflammation; to provide neuroprotection and to effectmemory enhancement. Thus, another aspect of the invention is theadministration of a therapeutically effective amount of an inventivecompound, or a physiologically acceptable salt thereof, to an individualor animal to provide a physiological effect.

In addition, some of the iodide and fluoride containing compounds, forexample, AM694 and AM1230, are potential radioactive probes which wouldbe useful for imaging in vivo the distribution of cannabinoid receptors.Further, azido containing compounds, for example, AM2212, AM2213 andAM1224, would be useful as affinity probes for characterizing bindingpockets of cannabinoid receptors.

Those skilled in the art will recognize, or be able to ascertain with nomore than routine experimentation, many equivalents to the specificembodiments of the invention disclosed herein. Such equivalents areintended to be encompassed by the scope of the invention.

1. A compound of the formula:

including any optical isomers, and physiologically acceptable salts thereof, wherein, Z may be in the 4-, 5-, 6- or 7-position and is selected from the group consisting of hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy and lower alkyl; X is selected from the group consisting of halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, and isothiocyano, and if Z is not hydroxy, methoxy or lower alkyl then X may also be selected from the group consisting of OTs and azido; R₁ is selected from the group consisting of a cyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, a bicyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, and if Z is not hydroxy, methoxy or lower alkyl then R₁ may also be selected from a heterocyclic ring attached to the indole nitrogen with a chain having one or two carbon atoms; R₂ is selected from the group consisting of H and lower alkyl; Y is selected from the group consisting of carbonyl and CH═CH (cis or trans); and R₃ is selected from the group consisting of phenyl; napthyl; 9-anthracenyl; adamantyl; pyrenyl; phenyl with no more than two substituents selected from the group consisting of halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano; napthyl with no more than two substituents selected from the group consisting of halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano; and 9-anthracenyl with no more than two substituents selected from the group consisting of halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano.
 2. The compound of claim 1, wherein Z is in the indole-6 position and is selected from the group consisting of H, NO₂, NH₂ and halogen.
 3. The compound of claim 1, wherein Y is C═O.
 4. The compound of claim 1, wherein R₂ is selected from the group consisting of H and CH₃.
 5. The compound of claim 1, wherein, Z may be in the 4-, 5-, 6- or 7-position and is selected from halogen, hydroxy, methoxy, or lower alkyl; X is selected from halogen, hydrogen, hydroxy, lower alkanoate, formyl, amino, cyano or isothiocyano; R₁ is selected from cyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms or bicyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms R₂ is selected from H or lower alkyl; Y is selected from carbonyl or CH═CH (cis or trans); and R₃ is selected from phenyl; naphthyl; 9-anthracenyl; phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; or 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.
 6. The compound of claim 1, wherein: Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano and phenyl; X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs and azido; R₁ is selected from a cyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, a bicyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, and a heterocyclic ring attached to the indole nitrogen with a chain having one or two carbon atoms R₂ is selected from H and lower alkyl; Y is selected from carbonyl and CH═CH (cis or trans); and R₃ is selected from phenyl; naphthyl; 9-anthracenyl; adamantyl; pyrenyl; phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano; naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano; and 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano.
 7. The compound of claim 1, wherein: Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano or phenyl; X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs or azido R₁ is selected from a cyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, a bicyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms or a heterocyclic ring attached to the indole nitrogen with a chain having one or two carbon atoms R₂ is selected from H or lower alkyl; Y is selected from carbonyl or CH═CH (cis or trans); and R₃ is selected from phenyl with two substituents independently selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.
 8. The compound of claim 1, wherein: Z is selected from hydrogen in the 6 position or halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy or lower alkyl in the 4-, 5-, 6- or 7-position; R₁ is a heterocyclic ring attached to the indole nitrogen with a chain having one or two carbon atoms; R₂ is selected from H or lower alkyl; Y is selected from carbonyl or CH═CH (cis or trans); X is OTs; and R₃ is selected from phenyl, naphthyl or 9-anthracenyl substituted with a first substituent selected from halogen, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido or isothiocyano and a second substituent selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido and isothiocyano; or R₃ is selected from phenyl, naphthyl or 9-anthracenyl substituted with one to four substituents groups independently selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido and isothiocyano; or R₃ is selected from adamantyl or pyrenyl either unsubstituted or substituted with no more than two substituents selected from halogen, nitro, nitroso, amino, hydroxy, azido, cyano and isothiocyano; and X is OTs.
 9. The compound of claim 1, wherein: Z is H in the 6 position; R₁ is piperidine attached to the indole 1 position with a chain having one or two carbon atoms; R₂ is hydrogen; Y is C═O; and R₃ is phenyl substituted with I and a second substituent selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.
 10. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the formula below, including any optical isomers, and physiologically acceptable salts thereof:

wherein in the compound, Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy or lower alkyl; X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano or isothiocyano, and if Z is not hydroxy, methoxy or lower alkyl then X may also be OTs or azido; R₁ is selected from a cyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, a bicyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, and if Z is not hydroxy, methoxy or lower alkyl then R1 may also be a heterocyclic ring attached to the indole nitrogen with a chain having one or two carbon atoms; R₂ is selected from H or lower alkyl; Y is selected from carbonyl or CH═CH (cis or trans); and R₃ is selected from phenyl; naphthyl; 9-anthracenyl; adamantyl; pyrenyl; phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; or 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.
 11. The pharmaceutical composition of claim 10, wherein: Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano or phenyl; X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs or azido R₁ is selected from a cyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, a bicyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms or a heterocyclic ring attached to the indole nitrogen with a chain having one or two carbon atoms; R₂ is selected from H or lower alkyl; Y is selected from carbonyl or CH═CH (cis or trans); and R₃ is selected from phenyl with two substituents independently selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.
 12. The pharmaceutical composition of claim 10, wherein: Z is selected from hydrogen in the 6 position or halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano, phenyl, hydroxy, methoxy or lower alkyl in the 4-, 5-, 6- or 7-position; R₁ is a heterocyclic ring attached to the indole nitrogen with a chain having one or two carbon atoms R₂ is selected from H or lower alkyl; Y is selected from carbonyl or CH═CH (cis or trans); X is OTs; and R₃ is selected from phenyl, naphthyl or 9-anthracenyl substituted with a first substituent selected from halogen, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido or isothiocyano and a second substituent selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido or isothiocyano; or R₃ is selected from phenyl, naphthyl or 9-anthracenyl substituted with one to four substituents groups independently selected from nitro, nitroso, amino, alkylamino, dialkylamino, azido or isothiocyano; or R₃ is selected from adamantyl or pyrenyl either unsubstituted or substituted with no more than two substituents selected from halogen, nitro, nitroso, amino, hydroxy, azido, cyano or isothiocyano.
 13. The pharmaceutical composition of claim 10, wherein: Z is H in the 6 position; R₁ is piperidine attached to the indole 1 position with a chain having one or two carbon atoms; R₂ is hydrogen; Y is C═O; and R₃ is phenyl substituted with I and a second substituent selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.
 14. The pharmaceutical composition of claim 10, wherein, Z may be in the 4-, 5-, 6- or 7-position and is selected from halogen, hydroxy, methoxy, or lower alkyl; X is selected from halogen, hydrogen, hydroxy, lower alkanoate, formyl, cyano or isothiocyano; R₁ is selected from a cyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms or a bicyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms R₂ is selected from H or lower alkyl; Y is selected from carbonyl or CH═CH (cis or trans); and R₃ is selected from phenyl; naphthyl; 9-anthracenyl; phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano; and 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano or isothiocyano.
 15. The pharmaceutical composition of claim 10, wherein, Z may be in the 4-, 5-, 6- or 7-position and is selected from hydrogen, halogen, nitro, nitroso, amino, alkylamino, dialkylamino, azido, cyano, isothiocyano and phenyl; X is selected from halogen; hydrogen; hydroxy, lower alkanoate, formyl, amino, cyano, isothiocyano, OTs and azido; R₁ is selected from a cyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, a bicyclic aliphatic ring attached to the indole nitrogen with a chain having one or two carbon atoms, and a heterocyclic ring attached to the indole nitrogen with a chain having one or two carbon atoms; R₂ is selected from H and lower alkyl; Y is selected from carbonyl and CH═CH (cis or trans); and R₃ is selected from phenyl; naphthyl; 9-anthracenyl; adamantyl; pyrenyl; phenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano; naphthyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano; and 9-anthracenyl with no more than two substituents selected from halogen, nitro, nitroso, amino, alkylamino, dialkylamino, hydroxy, methoxy, lower alkyl, azido, cyano and isothiocyano. 